Our Research Program aims to provide new insights into disease pathogenesis and to identify novel targets for therapy through the discovery and subsequent study of novel disease genes implicated in frontotemporal lobar degeneration (FTLD) and related disorders. It is unique in that it spans the full spectrum of disease research from gene discovery to therapy development, which allows immediate validation and application of novel research findings. While significant progress has been made in recent years to improve our understanding of the genetics of FTLD and the pathologies underlying this collection of neurodegenerative diseases affecting the frontal and temporal brain regions, its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. The most common pathological subtype of FTLD is characterized by pathological aggregates of the TAR DNA-binding protein 43 (FTLD-TDP), which is also the main pathological protein in patients with amyotrophic lateral sclerosis (ALS). As part of our Research Program we previously identified mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72) gene, the two most common causes of FTLD-TDP world-wide. We also identified the transmembrane protein 106 B gene (TMEM106B) as a major genetic modifier of disease onset and/or presentation in FTLD individuals with GRN and C9ORF72 mutations; however, other causal genes and modifying factors must exist. In this Research Program we will leverage our previous contributions to the field, novel resources and an extensive collection of patient samples to identify novel causal FTLD genes and genetic modifiers. Once new genes are identified, we will capitalize on the flexibility afforded by the R35 mechanism to immediately begin functional studies designed to expedite the translation of genetic discoveries to the patient's bedside. Through the discovery of novel FTLD disease genes and a better understanding of the factors that modify the expression of known disease genes such as GRN and C9ORF72, our Research Program will allow more accurate and earlier diagnosis, provide much needed guidance for clinicians involved in genetic counseling of mutation families, guide the inclusion of patients for future clinical trials and provide important novel insight into FTLD pathobiology. Our Program will also advance the development of biomarkers associated with disease phenotype or progression and provide novel targets for therapies.